Vitamin D analogues

ABSTRACT

The invention relates to 20(S)-vitamin D compounds having the following formula ##STR1## where U and R&#39; are as defined in the specification. The compounds have strong antiinflammatory and immunomodulating activity. There are also useful in the inhibition of proliferation of undesirable cells.

The application is a 371 of international application PCT/DK93/00351,filed Nov. 1, 1993.

This invention relates to a hitherto unknown class of compounds whichshows antiinflammatory and immunomodulating effects as well as strongactivity in inducing differentiation and inhibiting undesirableproliferation of certain cells, including cancer cells and skin cells,to pharmaceutical preparations containing these compounds, to dosageunits of such preparations, and to their use in the treatment andprophylaxis of hyperparathyroidism, particularly secondaryhyperparathyroidism associated with renal failure, of a number ofdisease states including diabetes mellitus, hypertension, ache,alopecia, skin ageing, imbalance in the immune system, of inflammatorydiseases such as rheumatoid arthritis and asthma, of diseasescharacterized by abnormal cell differentiation and/or cell proliferationsuch as e.g. psoriasis and cancer, for prevention and/or treatment ofsteroid induced skin atrophy, and for promoting osteogenesis andtreating osteoporosis.

The compounds of the present invention are derivatives of1α,25-dihydroxy-20-epi-vitamin D₃ as represented by the general formulaI ##STR2## in which formula the "¤" indicates that this carbon may bemodified, and the moiety U, substituting the 24-methylene of1α,25-dihydroxy-20-epi-vitamin D₃, stands for (CH₂)_(n) --Y--(CH₂)_(m),where n is 0, 1 or 2, m is 1 or 2, and Y is oxygen or sulphur; andderivatives formed by replacing either the 22-methylene or the23-methylene by an oxygen or by replacing 22- and 23-methylene with--CH═CH--; R' is methyl or ethyl; and in which one or more carbon atomsdirectly bonded to C-25 may optionally be substituted with one or morefluorine atoms.

Depending on the nature of the chain linking C-20 and C-25, thecompounds of the invention can comprise several isomeric forms (e.g. Ror S configuration at asymmetric carbon atoms, E or Z configuration ofdouble bonds). The invention covers all these diastereoisomers in pureform or as diastereomeric mixtures. In addition, derivatives of I inwhich one or more of the hydroxy groups are masked as groups which canbe reconverted to hydroxy groups in vivo are also within the scope ofthe invention.

The compounds I in which the hydroxyl group on carbon-25 is replaced byhydrogen are another type of prodrug. These compounds are relativelyinactive in vitro, but are converted to active compounds of formula I byenzymatic hydroxylation after administration to the patient.

It has been shown that 1α,25-dihydroxy-vitamin D₃ (1,25(OH)₂ D₃)influences the effects and/or production of interleukins (Muller, K. etal., Immunol. Lett. 17, 361-366 (1988)), indicating the potential use ofthis compound in the treatment of diseases characterized by adysfunction of the immune system, e.g. autoimmune diseases, AIDS, hostversus graft reactions, and rejection of transplants or other conditionscharacterized by an abnormal interleukin-1 production, e.g. inflammatorydiseases such as rheumatoid arthritis and asthma.

It has also been shown that 1,25(OH)₂ D₃ is able to stimulate thedifferentiation of cells and inhibit excessive cell proliferation (Abe,E. et al, Proc. Natl. Acad. Sci., U.S.A. 78, 4990-4994 (1981)), and ithas been suggested that this compound might be useful in the treatmentof diseases characterized by abnormal cell proliferation and/or celldifferentiation such as leukemia, myelofibrosis and psoriasis.

Also, the use of 1,25(OH)₂ D₃, or its pro-drug 1α-OH-D₃, for thetreatment of hypertension (Lind, L. et al, Acta Med. Scand. 222, 423-427(1987)) and diabetes mellitus (Inomata, S. et al, Bone Mineral 1,187-192 (1986)) has been suggested. Another indication for 1,25(OH)₂ D₃is suggested by the recent observation of an association betweenhereditary vitamin D resistance and alopecia: treatment with 1,25(OH)₂D₃ may promote hair growth (Editorial, Lancet, Mar. 4, 1989, p. 478).Also, the fact that topical application of 1,25(OH)₂ D₃ reduces the sizeof sebaceous glands in the ears of male Syrian hamsters suggests thatthis compound might be useful for the treatment of acne (Malloy, V. L.et al., the Tricontinental Meeting for Investigative Dermatology,Washington, 1989).

However, the therapeutic possibilities in such indications of 1,25(OH)₂D₃ are severely limited by the well known potent effect of this hormoneon calcium metabolism; elevated blood concentrations will rapidly giverise to hypercalcemia. Thus, this compound and its potent syntheticanalogues are not completely satisfactory for use as drugs in thetreatment of e.g. psoriasis, cancer or immune diseases which may requirecontinuous administration of the drug in relatively high doses.

A number of oxa- and thia-analogues of vitamin D₃ are known, includingthe 24-oxa-analogue of 24a-homo-1α,25-dihydroxy-vitamin D₃ and its26,27-dialkyl derivatives (European Patent Appln. No. 450 743A). Theoxa-compounds of the present invention differ structurally from thesecompounds in that they have the oxygen atom situated at a differentposition, i.e. 24a or 24b, in a further elongated side chain and/or inthat they possess the epi-configuration at the 20-position. In additiona number of 23-oxa and 23-thia compounds have been described(International patent application No. PCT/DK91/00091). Again these arestructurally distinct from the compounds of the present invention inthat they do not contain an oxygen or sulphur linking atom at position24 or further out (i.e. 24a or 24b) in the side chain.

The usefulness of a vitamin D analogue in the above mentionedindications is dependent not only upon a high activity demonstrated inan in vitro cell differentiation test, but also upon the fate of thecompound in the organism.

It has now been found that the compounds of the present invention showfavourable selectivity with respect to their effects on celldifferentiation in vitro and their calcemic effects in vivo, and at thesame time show high bioavailability as well as chemical and metabolicstability.

The selectivity of the compounds is illustrated by the fact that whilethe concentration needed to induce cell differentiation in a humanmonocytic rumour cell line is the same as or considerably lower thanthat needed of 1,25(OH)₂ D₃ to give the same effect, in vivo in rats thecompounds are less active than 1,25(OH)₂ D₃ in inducing hypercalciuriaand hypercalcemia.

The compounds of the invention are therefore especially suited for bothlocal and systemic treatment and prophylaxis of human and veterinarydisorders which are characterized by 1) abnormal cell proliferationand/or cell differentiation, such as certain dermatological disordersincluding psoriasis and certain cancer forms, 2) an imbalance in theimmune system, e.g. in autoimmune diseases, including diabetes mellitus,host versus graft reaction, and rejection of transplants; andadditionally for the treatment of inflammatory diseases, such asrheumatoid arthritis and asthma. Acne, alopecia, and hypertension areother conditions which may be treated with the compounds of theinvention. Finally, as thickening of the skin is observed after topicaltreatment with the compounds of the invention, these compounds may beuseful for treatment or prevention of skin ageing, includingphoto-ageing.

Because of the low tendency of the compounds to produce hypercalcemia oncontinued administration they are expected to be valuable for the longterm treatment of hyperparathyroidism (particularly secondaryhyperparathyroidism associated with renal failure) and for promotingosteogenesis and treating osteoporosis. For these indications thepresently described compounds have a higher therapeutic ratio than theprior art compounds.

The present compounds may be used in combination with otherpharmaceuticals. In the prevention of graft rejection and graft versushost reaction, a treatment with the present compounds may advantageouslybe combined with a cyclosporin treatment.

The compounds of formula I may conveniently be prepared from the vitaminD-derivative 1 (Tetrahedron, 43, 4609 (1987)) for example by the routesoutlined in Scheme 1. The routes used to prepare the key intermediatesII, some of which are known compounds, are not indicated on the Scheme,but some are illustrated in the preparations.

The symbol "¤" next to a carbon atom (cf. formula I) indicates than thismethylene (.sup.¤ CH₂) may optionally be replaced by a radical of thesame valency, as illustrated in the Preparations, Tables 1 and 2. Informulas II through VIII, n=0, 1 or 2, and the symbol Q is a surrogatefor atoms 22 and 23, i.e. ²²¤ CH₂ -²³¤ CH₂ of I or a group that can beconverted to it.

The following standard abbreviations are used throughout thisdisclosure: Me=methyl; Et=ethyl; Pr^(n) =n-propyl; Pr^(i) =isopropyl;Bu^(t) =tert-butyl=t-butyl; THP =tetra-hydro-4H-pyran-2-yl;THF=tetrahydrofuran: Ts=p-toluenesulphonyl;TBA=tetra-(n-butyl)-ammonium; TBDMS=tert-butyldimethylsilyl;DMF=N,N-dimethylformamide. ##STR3##

It should be noted that although the shown intermediates may havehydroxyl groups protected as tert-butyl-dimethylsilyl ethers, the scopeof the invention does not exclude the use of alternative hydroxylprotecting groups well known in the art (such as those described in T.W. Greene, "Protective groups in organic synthesis", Wiley, New York,1981), together with alternative reactions for deprotection.

O-Alkylation of II or S-alkylation of IV to give V (X =O from II; X=Sfrom IV) is achieved by treatment under basic conditions with a sidechain building block of general formula Z-R, in which Z is a leavinggroup such as a halogen (Cl, Br or I) or p-toluenesulphonyloxy ortrifluoromethanesulphonyloxy, and R is --(.sup.¤ CH₂)_(m) --²⁵C(OH)--(R')₂, in which R' is methyl or ethyl, and m=1 or 2, asappropriate ultimately to complete the side chain of I (such that"--(.sup.¤ CH₂)_(n) --X--(.sup.¤ CH₂)_(m) --" corresponds to "U"), oroptionally a radical which can be converted to this at any convenientlater stage (or over several stages). Thus R in compounds V, VI, VII andVIII does not necessarily have the same meaning along a particularsynthetic sequence. The conversion of R into --(.sup.¤ CH₂)_(m) --²⁵C(OH)--(R')₂ may well involve several steps and possibly involve atemporary protection of the sensitive triene system of the molecule,e.g. as the cyclo-adduct formed with sulphur dioxide. An alternative tothis route involves treatment of the intermediate III (Z is a leavinggroup as described above) under basic conditions with a side chainbuilding block HX-R, in which X is oxygen or sulphur and R is asdescribed above, to give the intermediate V. Apart from any necessarymodification within the side chain residue (R), the conversion of V to Iinvolves a photoisomerisation step and a desilylation step, analogous tothe steps used in the last stages of the synthesis of other vitamin Danalogues (see European patent No. 0 227 826).

It may be convenient to change the order of the alkylation reaction (dor e) and the photoisomerisation reaction (g), in which case the(5Z)-isomer of II, III, or IV is an intermediate.

The side chain building blocks, RZ, are either known compounds (severalare described in international patent application PCT/DK89/00079) or maybe prepared analogously to those described in PCT/DK89/00079. The R-Z istypically Br--(.sup.¤ CH₂)_(m) --²⁵ C(OY)--(R')₂ in which Y is ahydroxyl protecting group, e.g. tetrahydropyranyloxy ortrialkylsilyloxy. (Any such THP ethers R-Z, which are not described inPCT/DK89/00079, are readily prepared from the corresponding alcohol).

The side chain building blocks HX-R are also known compounds or may beprepared by methods analogous to those used to prepare such knowncompounds. The synthesis of new compounds R-Z or HX-R are illustrated inthe Preparations. For the case when m=1 R-Z may be Br--CH₂ CO₂ Bu^(t),and HX-R may be HSCH₂ CO₂ Et, and the ester group is converted byreaction e.g. with a Grignard reagent to ²⁵ C--(R')₂ OH.

As schematized above, at least for the "24-thia" compounds the routedoes not exclude deferring the alkylation of a thiol even as far as thelast step (e.g.) VIII, R=M→I).

The present compounds are intended for use in pharmaceuticalcompositions which are useful in the treatment of human and veterinarydisorders as described above.

The amount required of a compound of formula I (hereinafter referred toas the active ingredient) for therapeutic effect will, of course, varyboth with the particular compound, the route of administration and themammal under treatment. The compounds of the invention can beadministered by the parenteral, intra-articular, enteral or topicalroutes. They are well absorbed when given enterally and this is thepreferred route of administration in the treatment of systemicdisorders. In the treatment of dermatological disorders like psoriasis,topical or enteral forms are preferred.

In the treatment of respiratory diseases like asthma an aerosol ispreferred.

While it is possible for an active ingredient to be administered aloneas the raw chemical, it is preferable present it as a pharmaceuticalformulation. Conveniently, the active ingredient comprises from 1 ppm to0.1% by weight of the formulation.

By the term "dosage unit" is meant a unitary, i.e. a single dose whichis capable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically and chemically stable unitdose comprising either the active material as such or a mixture of itwith solid or liquid pharmaceutical diluents or carriers.

The formulations, both for veterinary and for human medical use, of thepresent invention comprise an active ingredient in association with apharmaceutically acceptable carrier therefore and optionally othertherapeutic ingredient(s). The carrier(s) must be "acceptable" in thesense of being compatible with the other ingredients of the formulationsand not deleterious to the recipient thereof.

The formulations include e.g. those in a form suitable for oral, rectal,parenteral (including subcutaneous, intramuscular and intravenous),intra-articular and topical administration.

The formulations may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units as capsules, sachets, tablets orlozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or non-aqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be administered in the form of a bolus,electuary or paste.

A tablet may be made by compressing or moulding the active ingredientoptionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing, in a suitable machine, the activeingredient in a free-flowing form such as a powder or granules,optionally mixed by a binder, lubricant, inert diluent, surface activeor dispersing agent. Moulded tablets may be made by moulding, in asuitable machine, a mixture of the powdered active ingredient andsuitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form of asuppository incorporating the active ingredient and a carrier such ascocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration convenientlycomprise a sterile oily or aqueous preparation of the active ingredientwhich is preferably isotonic with the blood of the recipient.

Formulations suitable for intra-articular administration may be in theform of a sterile aqueous preparation of the active ingredient which maybe in microcrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems may also be used to present the active ingredient forboth intra-articular and ophthalmic administration.

Formulations suitable for topical administration, including topicalapplication to the eye, include liquid or semi-liquid preparations suchas liniments, lotions, applicants, oil-in-water or water-in-oilemulsions such as creams, ointments or pastes; or solutions orsuspensions such as drops.

For asthma treatment inhalation of powder, self-propelling or sprayformulations, dispensed with a spray can, a nebulizer or an atomizer canbe used. The formulations, when dispensed, preferably have a particlesize in the range of 10 to 100 μ.

Such formulations are most preferably in the form of a finely comminutedpowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect may beachieved either by choice of a valve having the desired spraycharacteristics (i.e. being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. These self-propellingformulations may be either powder-dispensing formulations orformulations dispensing the active ingredient as droplets of a solutionor suspension.

Self-propelling powder-dispensing formulations preferably comprisedispersed particles of solid active ingredients, and a liquid propellanthaving a boiling point below 18° C. at atmospheric pressure. The liquidpropellant may be any propellant known to be suitable for medicinaladministration and may comprise one or more C₁ -C₆ -alkyl hydrocarbonsor halogenated C₁ -C₆ -alkyl hydrocarbons or mixtures thereof;chlorinated and fluorinated C₁ -C₆ -alkyl hydrocarbons are especiallypreferred. Generally, the propellant constitutes 45 to 99.9% w/w of theformulation whilst the active ingredient constitutes 1 ppm to 0.1% w/w,of the formulation.

In addition to the aforementioned ingredients, the formulations of thisinvention may include one or more additional ingredients such asdiluents, buffers, flavouring agents, binders, surface active agents,thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate(including anti-oxidants), emulsifying agents and the like. Thecompositions may further contain other therapeutically active compoundsusually applied in the treatment of the above mentioned pathologicalconditions.

The present invention further concerns a method for treating patientssuffering from one of the above pathological conditions, said methodconsisting of administering to a patient in need of treatment aneffective amount of one or more compounds of formula I, alone or incombination with one or more other therapeutically active compoundsusually applied in the treatment of said pathological conditions. Thetreatment with the present compounds and/or with further therapeuticallyactive compounds may be simultaneous or with intervals.

In the treatment of systemic disorders daily doses of from 0.1-100 μg,preferably from 0.2-25 μg, of a compound of formula I are administered.In the topical treatment of dermatological disorders, ointments, creamsor lotions containing from 0.1-500 μg/g, and preferably from 1-100 μg/g,of a compound of formula I are administered. The oral compositions areformulated, preferably as tablets, capsules, or drops, containing from0.05-50 μg, preferably from 0.1-25 μg, of a compound of formula I, perdosage unit.

The invention will now be further described in the followingnon-limiting Preparations and Examples:

PREPARATIONS AND EXAMPLES General

The exemplified compounds I are listed in Table 1. The intermediates ofScheme I referred to in the Preparations are to be identified by numberswith the corresponding formulae in Table 2. These are used to illustratetypical syntheses of the exemplified compounds I.

For nuclear magnetic resonance spectra (300 MHz) chemical shift values(δ) are quoted in ppm for deuteriochloroform solutions (except whereotherwise stated) relative to internal tetramethylsilane (δ=0) orchloroform (δ=7.25). The value for a multiplet, either defined (doublet(d), triplet (t), quartet (q)) or not (m) at the approximate mid pointis given unless a range is quoted (s=singlet, b=broad). Couplingconstants (J) are given in Hertz, and are sometimes approximated to thenearest unit.

Ether is diethyl ether, and was dried over sodium. THF was dried oversodium-benzophenone. Petroleum ether refers to the pentane fraction. Ifnot specified, % means v/v %. Reactions were run at room temperatureunless otherwise noted. The work-up procedure referred to involvesdilution with the specified solvent (otherwise the organic reactionsolvent), extraction with water and then brine, drying over anhydrousMgSO₄, and concentration in vacuo to give a residue. Chromatography wasperformed on silica gel.

                  TABLE 1                                                         ______________________________________                                        Examples of Compounds of formula I (Details are                               provided for compounds where an Example Number                                is given; the other compounds may be prepared                                 using analogous reaction sequences).                                                         Surrogate                                                      Com-           for                                                            pound  Ex.     methylene-                                                     No.    No.                                                                    22                                                                            23                           U            R'                                  ______________________________________                                        101    1       CH.sub.2                                                                              CH.sub.2                                                                            O--CH.sub.2  Me                                  102    2       CH.sub.2                                                                              CH.sub.2                                                                            O--CH.sub.2  Et                                  103    3       CH.sub.2                                                                              CH.sub.2                                                                            O--CH.sub.2 --CH.sub.2                                                                     Et                                  104    4       CH.sub.2                                                                              CH.sub.2                                                                            O--CH.sub.2 --CF.sub.2                                                                     Et                                  107    5       CH.sub.2                                                                              CH.sub.2                                                                            S--CH.sub.2  Me                                  106    6       CH.sub.2                                                                              CH.sub.2                                                                            S--CH.sub.2  Et                                  105    7       CH*     CH*   CH.sub.2 --O--CH.sub.2                                                                     Me                                  108    8       CH.sub.2                                                                              CH.sub.2                                                                            CH.sub.2 --O--CH.sub.2                                                                     Me                                  109    --      O       CH.sub.2                                                                            CH.sub.2 --O--CH.sub.2                                                                     Me                                  110    --      CH.sub.2                                                                              O     CH.sub.2 --CH.sub.2 --O--CH.sub.2                                                          Me                                  111    --      CH.sub.2                                                                              CH.sub.2                                                                            S--CH.sub.2 --CH.sub.2                                                                     Et                                  112    --      CH.sub.2                                                                              CH.sub.2                                                                            S--CH.sub.2 --CF.sub.2                                                                     Et                                  113    --      CH.sup.+                                                                              CH.sup.+                                                                            CH.sub.2 --O--CH.sub.2                                                                     Me                                  ______________________________________                                         *(E) configuration of 22,23double bond.                                       .sup.+ (Z) configuration of 22,23double bond.                            

                                      TABLE 2                                     __________________________________________________________________________    Examples of intermediates of formula II through VIII (Scheme 1) (Details      are provided for compounds where a Preparation Number is given; the           other compounds may be prepared using analogous reaction sequences when       not otherwise noted)                                                          Compound                                                                            Prep.                                                                   No.   No.                                                                              Type                                                                             Q      (.sup.¤ CH.sub.2).sub.n                                                     XR or Z                                             __________________________________________________________________________     4     1C                                                                              II CH.sub.2 --CH.sub.2                                                                  --     --                                                   7     2C                                                                              II CH.sub.2 --CH.sub.2                                                                  CH.sub.2                                                                             --                                                  10     3C                                                                              II CH.sub.2 --CH.sub.2                                                                  CH.sub.2 --CH.sub.2                                                                  --                                                  11    --.sup.#                                                                         II CH═CH*                                                                           CH.sub.2                                                                             --                                                  12     4 III                                                                              CH.sub.2 --CH.sub.2                                                                  --     OTs                                                 13     5 III                                                                              CH.sub.2 --CH.sub.2                                                                  CH.sub.2                                                                             OTs                                                 14     6 V  CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 CO.sub.2 Bu.sup.t                       15    10 V  CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 --C(OH)Me.sub.2                         16    11 V  CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 --C(OH)Et.sub.2                         17     8 V  CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 --CH.sub.2 C(OH)Et.sub.2                18     9 V  CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 CF.sub.2 --C(OH)Et.sub.2                19     7 V  CH═CH*                                                                           CH.sub.2                                                                             O--CH.sub.2 --CO.sub.2 Bu.sup.t                     20    12 V  CH═CH*                                                                           CH.sub.2                                                                             O--CH.sub.2 --C(OH)Me.sub.2                         21    13 VI CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 --C(OH)Me.sub.2                         22    14 VI CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 --C(OH)Et.sub.2                         23    15 VI CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 CH.sub.2 --C(OH)Et.sub.2                24    16 VI CH.sub.2 --CH.sub.2                                                                  --     O--CH.sub.2 CF.sub.2 --C(OH)Et.sub.2                25    17 VI CH═CH*                                                                           CH.sub.2                                                                             O--CH.sub.2 --C(OH)Me.sub.2                         26    24 V  CH.sub.2 --CH.sub.2                                                                  --     S--CH.sub.2 --C(OH)Et.sub.2                         27    26 VI CH.sub.2 --CH.sub.2                                                                  --     S--CH.sub.2 C(OH)Et.sub.2                           28    18 II O--CH.sub.2                                                                          CH.sub.2                                                                             --                                                  29    -- V  O--CH.sub.2                                                                          CH.sub.2                                                                             O--CH.sub.2 --CO.sub.2 Bu.sup.t                     30    -- V  O--CH.sub.2                                                                          CH.sub.2                                                                             O--CH.sub.2 --C(OH)Me.sub.2                         31    -- VI O--CH.sub.2                                                                          CH.sub.2                                                                             O--CH.sub.2 --C(OH)Me.sub.2                         32    19 II CH.sub.2 --O                                                                         CH.sub.2 --CH.sub.2                                                                  --                                                  33    -- V  CH.sub.2 --O                                                                         CH.sub.2 --CH.sub.2                                                                  O--CH.sub.2 --CO.sub.2 Bu.sup.t                     34    -- V  CH.sub.2 --O                                                                         CH.sub.2 --CH.sub.2                                                                  O--CH.sub.2 --C(OH)Me.sub.2                         35    -- VI CH.sub.2 --O                                                                         CH.sub.2 --CH.sub.2                                                                  O--CH.sub.2 --C(OH)Me.sub.2                         36    20 III                                                                              CH.sub.2 --CH.sub.2                                                                  --     Br                                                  37    21 III                                                                              CH.sub.2 --CH.sub.2                                                                  CH.sub.2                                                                             Br                                                  38    22 V  CH.sub.2 --CH.sub.2                                                                  --     S--CH.sub.2 --CO.sub.2 Et                           39    23 V  CH.sub.2 --CH.sub.2                                                                  --     S--CH.sub.2 --C(OH)Me.sub.2                         40    25 VI CH.sub.2 --CH.sub.2                                                                  --     S--CH.sub.2 --C(OH)Me.sub.2                         41    27 V  CH.sub.2 --CH.sub.2                                                                  CH.sub.2                                                                             O--CH.sub.2 --CO.sub.2 Bu.sup.t                     42    28 V  CH.sub.2 --CH.sub.2                                                                  CH.sub.2                                                                             O--CH.sub.2 --C(OH)Me.sub.2                         43    29 VI CH.sub.2 --CH.sub.2                                                                  CH.sub.2                                                                             O--CH.sub.2 --C(OH)Me.sub.2                         __________________________________________________________________________     The missing compound numbers refer to intermediates between compounds 1       and II and are described in the appropriate Preparations.                     .sup.# Previously described compound.                                         *(E) configuration of 22,23double bond.                                  

General Procedure 1

A: Conversion of a tosylate to a nitrile, followed by

B: Reduction to an aldehyde, and then C: Reduction to an alcohol offormula II (Preparations 1-3).

A: To a solution of the tosylate (7.50 mmol) in DMF (80 ml) at roomtemperature was added potassium cyanide (4.97 g, 76.2 mmol) and18-Crown-6 (0.50 g, 1.89 mmol). After stirring for 5 h at 50° C. thereaction mixture was poured into water and extracted twice with ethylacetate. The combined organic layers was washed several times withwater, dried over MgSO₄ and concentrated. The residue was purified bychromatography (75 g silica gel; 5% EtOAc in petroleum ether as eluant)to give the nitrile.

B: To a solution of the nitrile from Part A (7 mmol) in dry ether (30ml) at -78° C. was added a 1.0M solution of diisobutylaluminium hydridein toluene (9.0 ml). The reaction mixture was warmed to 0° C. After 2 hmore diisobutylaluminium hydride (6.0 ml) was added and the mixture wasstirred for an additional hour at 0° C. The mixture was quenched bysaturated aq. NH₄ Cl (5 ml) and methanol (5 ml) and extracted with ethylacetate. The organic phase was washed with water (twice), and brine andthen dried over MgSO₄ and concentrated in vacuo. Flash chromatography(75 g silica gel; 5% EtOAc in petroleum ether as eluant) to give thealdehyde.

C: A stirred, ice-cooled solution of the aldehyde from Part B (3.22mmol) in THF (10 ml) and ethanol (35 ml) was treated with sodiumborohydride (0.14 g, 3.54 mmol). After 30 minutes the reaction mixturewas partitioned between ethyl acetate and water, and the organic layerwas washed with brine and dried. Concentration in vacuo gave the alcoholof formula II.

Preparation 1A

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-cyanomethyl-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 2)

The tosylate used is 1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(R)-(p-toluenesulphonyloxymethyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (5.47 g). Compound 2: δ 0.05 (m, 12H), 0.54 (s, 3H),0.85 (s, 9H), 0.89 (s, 9H), 1.09 (d, 3H), 1.00-2.03 (m, 13H), 2.08 (bt,1H), 2,31 (bd, 1H), 2.43 (m, 2H), 2.54 (dd, 1H), 2.88 (m, 1H), 4.21 (m,1H), 4.52 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.43 (d,1H).

Preparation 1B

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-formylmethyl-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 3)

The nitrile used is compound 2 (4.06 g). Compound 3: δ 0.05 (m, 12H),0.57 (s, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 0.94 (d, 3H), 1.10-2.12 (m,14H), 2.17-2.37 (m, 2H), 2.55 (dd, 1H), 2.65 (dd, 1H), 2.87 (dd, 1H),4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.83 (d, 1H),6.44 (d, 1H), 9.74 (dd, 1H).

Preparation 1C

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(2'-hydroxyethyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 4)

The aldehyde used is compound 3 (1.89 g). Compound 4: δ 0.05 (m, 12H),0.56 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.86 (d, 3H), 1.10-2.10 (m,17H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.87 (m, 1H), 3.55-3.80 (m, 2H),4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H),6.45 (d, 1H).

Preparation 2A

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(2'-cyanoethyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 5)

The tosylate used is 1(S), 3(S)-bis-tert-butyldimethylsilyloxy-20(S)-(2'-p-toluenesulphonyloxyethyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 12, Preparation 4) (5.57 g).

Preparation 2B

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(2'-formylethyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 6)

The nitrile used is compound 5 (4.16 g). Compound 6: δ 0.05 (bs, 12H),0.55 (s, 3H), 0.85 (d, 3H), 0.85 (s, 9H), 0.88 (s, 9H), 1.20-2.05 (m,16H), 2.25-2.60 (m, 4H), 2.87 (dd, 1H), 4.20 (m, 1H), 4.52 (m, 1H), 4.93(m, 1H), 4.97 (m, 1H), 5.81 (d, 1H), 6.44 (d, 1H), 9.77 (t, 1H).

Preparation 2C

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(3'-hydroxy-1'-propyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 7H)

The aldehyde used is compound 6 (1.94 g). Compound 7: δ 0.05 (m, 12H),0.53 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.86 (d, 3H), 1.15-2.05 (m,19H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.87 (m, 1H), 3.55-3.70 (m, 2H),4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H),6.45 (d, 1H).

Preparation 3A

1(S), 3 (R)-bis-tert-butyldimethylsilyloxy-20(S) -(3'-cyano-1'-propyl)-9,10-secopregna-5(E), 7(E), 10(19)-triene (Compound 8)

The tosylate used is1(S),3(S)-bis-tert-butyldimethylsilyloxy-20(S)-(3'-p-toluenesulphonyloxy-1'-propyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 13, Preparation 5) (5.68 g).

Preparation 3B

1(S), 3(R) -bis-tert-butyldimethylsilyloxy-20(S)-(3'-formyl-1'-propyl)-9,10-secopregna-5(E), 7(E), 10(19)-triene (Compound 9)

The nitrile used is compound 8 (4.26 g). Compound 9: δ 0.05 (bs, 12H),0.55 (s, 3H), 0.85 (d, 3H), 0.85 (s, 9H), 0.88 (s, 9H), 1.05-2.05 (m,18H), 2,35 (bd, 1H), 2.40 (m, 2H), 2.55 (dd, 1H), 2.87 (dd, 1H), 4.20(m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.97 (m, 1H), 5.81 (d, 1H), 6.44(d, 1H), 9.77 (t, 1H).

Preparation 3C:

1(S), 3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(4'-hydroxy-1'-butyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 10)

The aldehyde used is compound 9 (1.98 g). Compound 10: δ 0.05 (m, 12H),0.53 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.84 (d, 3H), 1.05-2.05 (m,21H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.87 (m, 1H), 3.64 (t, 2H), 4.21 (m,1H), 4.53 (m, 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d,1H).

General Procedure 2

Conversion of an alcohol of formula II to a tosylate of formula III(Preparations 4 and 5)

The alcohol (1.19 mmol) was dissolved in dichloromethane (20 ml) andpyridine (1 ml), and the solution was stirred and ice-cooled during theaddition of p-toluenesulphonyl chloride (0.81 g, 4.25 mmol). Thereaction mixture was allowed to stand at room temperature overnightbefore being partitioned between ethyl acetate and water. The organiclayer was washed consecutively with saturated cupric sulphate solution(twice), water, 5% sodium hydrogen carbonate solution, and brine, andthen dried and concentrated in vacuo. Flash chromatography (50 g silicagel, 2% to 5% ethyl acetate in petroleum ether as eluant) to give thetosylate.

Preparation 4

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(2'-p-toluenesulphonyloxyethyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 12)

The alcohol used is compound 4 (0.70 g). Compound 12: δ 0.05 (m, 12H),0.47 (s, 3H), 0.77 (d, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.10-2.05 (m,16H), 2.29 (bd, 1H), 2.43 (s, 3H), 2.54 (dd, 1H), 2.85 (d, 1H), 4.08 (m,2H), 4.20 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.97 (m, 1H), 5.80 (d,1H), 6.43 (d, 1H), 7.33 (d, 2H), 7.78 (d, 2H).

Preparation 5

1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(3'-p-toluenesulphonyloxy-1'-propyl)-9,10-secopregna-5(E),7(E),10(19)-triene(Compound 13)

The alcohol used is compound 7 (0.72 g).

General Procedure 3

O-alkylation of Compounds II to give Compound V (Preparations 6, 7 and27)

A mixture of the alcohol II (2.55 mmol), t-butyl bromoacetate (1.15 ml,7.65 mmol) and a catalytic amount (200 mg) of tetra-n-butylammoniumbromide was stirred vigorously overnight, at room temperature, intoluene (40 ml)/NaOH (aqueous, 20%, 30 ml). The reaction mixture waspartitioned between ethyl acetate and water, and the organic layer waswashed with brine, dried over MgSO₄, and evaporated in vacuo.Purification of the residue by chromatography (50 g silica gel, 5% EtOAcin petroleum ether as eluant) gave the compound V.

Preparation 6: Compound 14

The alcohol used is compound 4 (1.50 g). Compound 14: δ 0.05 (m, 12H),0.55 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.82-0.92 (d, 3H), 1.47 (s,9H), 1.00-2.10 (m, 16H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.86 (m, 1H),3.53 (m, 2H), 3.93 (m, 2H), 4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m, 1H),4.97 (m, 1H), 5.81 (d, 1H), 6.44 (d, 1H).

Preparation 7: Compound 19

The alcohol used is compound 11 (1.53 g). Compound 19: δ 0.05 (m, 12H),0.51 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.11 (d, 3H), 1.47 (s, 9H),1.05-2.15 (m, 14H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.85 (m, 1H), 3.92 (s,2H), 4.02 (m, 2H), 4.21 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.97 (m,1H), 5.47 (m, 1H), 5.60 (dd, 1H), 5.80 (d, 1H), 6.44 (d, 1H).

General Procedure 4

Conversion of Compounds III to Compounds V (Preparations 8, 9, 18, 19and 22)

Method A (X=O)

To a solution of the side chain building block R-XH (0.372 mmol),potassium hydride (0.187 ml, 20% suspension in oil) and 18-Crown-6 (98mg) in dry THF (6 ml), the compound III (0.186 mmol) is added. Themixture is stirred at room temperature overnight, diluted with ethylacetate and extracted twice with water and brine. After drying overMgSO₄ and the removal of solvent in vacuo, the product is purified bychromatography (30 g silica gel; 10% EtOAc in petroleum ether as eluant)to give the compound V.

Method B (X=S):

Sodium hydride dispersion (55% in oil, 60 mg) was washed with petroleumether (3×2 ml) under an atmosphere of argon. A solution of R-XH (0.82mmol) in DMF (dried over molecular sieves) (2 ml) was added, followed byCompound III (ca. 0.5 mmol) in DMF (1 ml). After 30 minutes the reactionmixture was worked up with ether (60 ml). The residue was purified bychromatography to give V.

Preparation 8: Compound 17

Using method A, the side chain building block R-XH is3-ethyl-1,3-pentanediol (91 mg), and the compound III is compound 12(139 mg). Compound 17: δ 0.05 (s, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.89(s, 9H), 0.80-0.90 (m, 9H), 1.51 (m, 4H), 1.71 (t, 2H), 0.75-2.10 (m,16H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.86 (m, 1H), 3.22 (s, 1H), 3.44 (m,2H), 3.62 (m, 2H), 4.21 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.97 (m,1H), 5.81 (m, 1H), 6.44 (d, 1H).

4,4-difluoro-3-ethyl-3-trimethylsilyloxy-5-hexene

A heterogenous solution of acid-washed zinc powder (4.74 g, 72,5 mmol),3-pentanone (3.84 ml, 36.4 mmol), and dry THF (25 ml) was cooled to 0°C. in an ice-water bath, and a mixture of 3-bromo-3,3-difluoropropene(6.00 g, 38.2 mmol) in dry THF (10 ml) was slowly added. The reactionmixture was allowed to stand at room temperature overnight. Then,aqueous hydrochloric acid (5%, 30 ml) was added to the reaction mixture,which was stirred for 5 minutes. Excess zinc was removed by filtrationand washed with ether. The organic phase was washed with saturatedsodium bicarbonate solution, water (twice), dried over MgSO₄ andconcentrated. This oil was dissolved in dichloromethane (50 ml), andtriethylamine (7.05 ml, 50.8 mmol) and 4-(N,N-dimethylamino)-pyridine(250 mg) are added. The reaction mixture was cooled to 0° C. andtrimethylsilyl chloride (6.42 ml, 50.8 mmol) was added dropwise, and themixture was stirred at room temperature overnight. The reaction mixturewas poured into water and extracted twice with ether. The combinedorganic layers were washed several times with water, dried over MgSO₄,and evaporated in vacuo. The residue was purified by chromatography (50g silica gel; 2% EtOAc in petroleum ether as eluant) to give thecompound as a colourless oil, δ 0.13 (s, 9H), 0.89 (m, 6H), 1.5-1.8 (m,4H), 5.43 (m, 1H), 5.63 (m, 1H), 5.92-6.13 (m, 1H).

2,2-difluoro-3-ethyl-3-trimethylsilyloxy-pentanal

4,4-difluoro-3-ethyl-3-trimethylsilyloxy-5-hexene (2.00 g, 8.88 mmol)was dissolved in dichloromethane (80 ml), and the solution was cooled to-78° C. A gaseous mixture of O₃ in O₂ was passed into the solution untilit became blue. Nitrogen was bubbled through the solution to removeexcess ozone, dimethyl sulfide (3 ml) was added, and the solution wasbrought slowly to room temperature. Following ozonide decomposition,dichloromethane was added, and the organic layer was washed with water(twice), dried over CaCl₂ and concentrated under reduced pressure. Flashchromatography (50 g silica gel; 5% EtOAc in petroleum ether as eluant)to give the title compound as a pale yellow oil, δ 0.14 (s 9H), 0.91 (m,6H), 1.64 (m, 2H), 1.85 (m, 2H), 9.55 (t, 1H).

2,2-difluoro-3-ethyl-3-trimethylsilyloxy-pentane-1-ol

A stirred, ice-cooled solution of2,2-difluoro-3-ethyl-3-trimethylsilyloxy-pentanal (1.45 g, 6.08 mmol) inTHF (5 ml) and ethanol (15 ml) was treated with sodium borohydride (2.76mg, 7.30 mmol). After 30 minutes the reaction mixture was partitionedbetween ethyl acetate and water, and the organic layer was washed withbrine, dried over MgSO₄ and concentrated. Flash chromatography (50 gsilica gel; 10% EtOac in petroleum ether as eluant) afforded the titlecompound as a colourless oil, δ 0.15 (s, 9H), 1.36 (t, 6H), 2.48 (m,1H), 3.93 (m, 2H).

Preparation 9: Compound 18

Using method A, the side chain building block R-XH is2,2-difluoro-3-ethyl-3-trimethylsilyloxy-pentane-1-ol (289 mg) and thecompound III is compound 12 (200 mg). The isolation procedure gave riseto desilylation in the side chain.

Compound 18: δ 0.05 (s, 12H), 0.54 (s, 3H), 0.86 (d, 3H), 0.86 (s, 9H),0.90 (s, 9H), 0.93 (t, 6H), 1.10-2.10 (m, 20H), 2.30 (bd, 1H), 2.55 (dd,1H), 2.62 (s, 1H), 2.87 (m, 1H), 3.57 (m, 2H), 3.79 (m, 2H), 4.21 (m,1H), 4.53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.81 (m, 1H), 6.44 (d,1H).

General Procedure 5

Modification of "XR" in Compounds V: Reaction of an ester functionwithin "R" with an organometallic reagent to give an alcohol(Preparations 10, 11, 12, 23, 24 and 28)

To a solution of the ester V (0.306 mmol) in dry ether (5 ml) at -40° C.was added dropwise the organometallic reagent. The mixture was stirredat -40° C. for 1/2 h and at 0° C. for 1 h. The reaction mixture ispoured into a stirred ice-cooled mixture of ether (25 ml) and ammoniumchloride (1.5 g) in water (10 ml). The ether layer is separated, and theaqueous layer is extracted with more ether (2×50 ml). The combined etherlayers are washed consecutively with water (2×50) and saturated aqueoussodium chloride (50 ml), dried and concentrated in vacuo. Flashchromatography (30 g silica gel, 10% increasing to 30% ether inpetroleum ether as eluant) gave the alcohol V.

Preparation 10: Compound 15

The ester V is compound 14 (215 mg), and the organometallic reagent isMeMgBr (3M solution in ether, 1.0 ml). Compound 15: δ 0.05 (m, 12H),0.55 (s, 3H), 0.85 (s, 9H), 0.86 (d, 3H), 0.89 (s, 9H), 1.19 (s, 6H),1.00-2.10 (m, 16H), 2.30 (bd, 1H), 2.32 (s, 1H), 2.55 (dd, 1H), 2.87 (m,1H), 3.22 (m, 2H), 3.50 (m, 2H), 4.21 (m, 1H), 4.53 (m, 1H), 4.93 (m,1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation 11: Compound 16

The ester V is compound 14 (215 mg), and the organometallic reagent isEtMgBr (3M solution in ether, 1.0 ml). Compound 16: δ 0.05 (m, 12H),0.55 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.82-0.92 (m, 9H), 1.50 (m,4H), 1.10-2.10 (m, 16H), 2.13 (s, 1H), 2.31 (bd, 1H), 2.55 (dd, 1H),2.87 (m, 1H), 3.25 (m, 2H), 3.46 (m, 2H), 4.21 (m, 1H), 4.53 (m, 1H),4.93 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation 12: Compound 20

The ester V is compound 19 (219 mg), and the organometallic reagent isMeMgBr (3M solution in ether, 1.0 ml). Compound 20: δ 0.05 (m, 12H),0.51 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 0.94 (d, 3H), 1.18 (s, 6H),1.15-2.15 (m, 14H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.85 (m, 1H), 3.22 (s,2H), 3.96 (m, 2H), 4.21 (m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.97 (m,1H), 5.47 (m, 1H), 5.54 (dd, 1H), 5.80 (d, 1H), 6.43 (d, 1H).

General Procedure 6

Isomerization of Compounds V to the Corresponding Compounds VI(Preparations 13 to 17, 25, 26 and 29)

A solution of the compound V (ca. 0.2 g), anthracene (200 mg) andtriethylamine (0.3 ml) in dichloromethane (15 ml) under nitrogen in aPyrex flask was irradiated with light from a high pressure ultravioletlamp, type TQ718Z2 (Hanau) at about 10° C. for 30 minutes. The reactionmixture was filtered, concentrated in vacuo and purified bychromatography to give the compound VI.

Preparation 13: Compound 21

The compound V is compound 15, and the chromatographic conditions were:30 g silica gel, 10% ether in petroleum ether as eluant. Compound 21: δ0.05 (m, 12H), 0.54 (s, 3H), 0.87 (s, 18H), 0.82-0.92 (d, 3H), 1.19 (s,6H), 1.10-2.05 (m, 16H), 2.20 (dd, 1H), 2.32 (s, 1H), 2.44 (dd, 1H),2.82 (m, 1H), 3.23 (m, 2H), 3.50 (m, 2H), 4.18 (m, 1H), 4.36 (m, 1H),4.86 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H), 6.23 (d, 1H).

Preparation 14: Compound 22

The compound V is compound 16, and the chromatographic conditions were:30 g silica gel, 10% ether in petroleum ether as eluant. Compound 22: δ0.05 (m, 12H), 0.53 (s, 3H), 0.87 (s, 18H), 0.82-0.92 (m, 9H), 1.52 (m,4H), 1.00-2.05 (m, 16H), 2.13 (s, 1H), 2.21 (dd, 1H), 2.44 (dd, 1H),2.82 (m, 1H), 3.24 (m, 2H), 3.46 (m, 2H), 4.18 (m, 1H), 4.36 (m, 1H),4.85 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H), 6.22 (d, 1H).

Preparation 15: Compound 23

The compound V is compound 17, and the chromatographic conditions were:30 g silica gel, 10% ether in petroleum ether as eluant. Compound 23: δ0.05 (m, 12H), 0.52 (s, 3H), 0.87 (s, 18H), 0.75-0.95 (m, 9H), 1.71 (t,2H), 1.15-2.05 (m, 20H), 2.20 (dd, 1H), 2.43 (dd, 1H), 2.81 (m, 1H),3.22 (bs, 1H), 3.43 (m, 2H), 3.61 (m, 2H), 4.18 (m, 1H), 4.36 (m, 1H),4.85 (m, 1H), 5.17 (m, 1H), 6.00 (d, 1H), 6.22 (m, 1H).

Preparation 16: Compound 24

The compound V is compound 18, and the chromatographic conditions were:30 g silica gel, 10% ether in petroleum ether as eluant. Compound 24: δ0.05 (m, 12H), 0.53 (m, 3H), 0.87 (s, 18H), 0.88 (d, 3H), 0.92 (m, 12H),1.10-2.10 (m, 20H), 2.21 (dd, 1H), 2.43 (dd, 1H), 2.63 (s, 1H), 2.82 (m,1H), 3.56 (m, 2H), 3.80 (m, 2H), 4.18 (m, 1H), 4.36 (m, 1H), 4.85 (m,1H), 5.17 (m, 1H), 6.00 (d, 1H), 6.22 (d, 1H).

Preparation 17: Compound 25

The compound V is compound 20, and the chromatographic conditions were:30 g silica gel, 10% increasing to 30% ether in petroleum ether aseluant. Compound 25: δ 0.05 (m, 12H), 0.54 (s, 3H), 0.87 (s, 18H), 0.94(d, 3H), 1.18 (s, 6H), 1.10-2.15 (m, 14H), 2.20 (dd, 1H), 2.32 (s, 1H),2.44 (dd, 1H), 2.82 (m, 1H), 3.22 (s, 2H), 3.96 (m, 2H), 4.18 (m, 1H),4.36 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 5.47 (m, 1H), 5.54 (dd, 1H),6.01 (d, 1H), 6.23 (d, 1H).

Preparation 18: Compound 28

The compound was prepared by O-alkylation of 1(S),3(R)-bis-tert-butyldimethylsilyloxy-20(R)-hydroxy-9,10-secopregna-5(E),7(E),10(19)-trienewith KH and allyl bromide in THF followed by conversion of the productto the SO₂ -adduct by reaction with liquid SO₂. Ozonolysis of the sidechain double bond with reductive work-up (O₃ in CH₂ Cl₂ -MeOH followedby NaBH₄) and finally cleavage of the SO₂ (NaHCO₃, boiling ethanol) gavethe title compound.

Preparation 19: Compound 32

This compound was prepared by the method of Preparation 18, but using1(S),3(R)-bis-tert-butyldimethyl-silyloxy-20(R)-hydroxymethyl-9,10-secopregna-5(E),7(E),(10(19)-trieneas starting material.

General Procedure 7

Conversion of an alcohol of formula II to a bromide of formula III(Preparations 20 and 21)

Triphenylphosphine (507 mg, 1.93 mmol) and pyridine (0.64 ml, 7.73 mmol)was added to a solution of the alcohol (ca. 1.5 mmol) in dichloromethane(10 ml) at 0° C. under an argon atmosphere. This was followed bydropwise addition of a carbon tetrabromide solution (640 mg, 1.93 mmol)in dichloromethane (10 ml) under stirring. After stirring for 1 hour at25° C. the solvent is removed under reduced pressure and the residuewashed with ethyl acetate/petroleum ether (2:8) (2×20 ml) to removemajority of Ph₃ PO. The organic layer was washed with water and brine,dried over MgSO₄, and concentrated. The residue is purified bychromatography (30 g silica gel, 5% ethyl acetate in petroleum ether aseluant) to give the desired compound as an oil.

Preparation 20:

1(S), 3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(2'-bromoethyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 36)

The alcohol used is compound 4 (0.90 g). Compound 36: δ 0.05 (m, 12H),0.57 (s, 3H), 0.86 (s, 9H), 0.90 (s, 9H), 0.85-0.92 (d, 3H), 1.00-2.50(m, 17H), 2.55 (dd, 1H), 2.88 (m, 1H), 3.30-3.58 (m, 2H), 4.21 (m, 1H),4.53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.45 (d, 1H).

Preparation 21

1(S), 3(R)-bis-tert-butyldimethylsilyloxy-20(S)-(3'-bromo-1'-propyl)-9,10-secopregna-5(E),7(E), 10(19)-triene (Compound 37)

The alcohol used is compound 7 (0.90 g).

Preparation 22: Compound 38

Using General Procedure 4, method B, R-XH is ethyl mercaptoacetate (0.23ml) and the compound III is compound 36 (918 mg).

Compound 38: δ 0.05 (m, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H),0.85-0.92 (d, 3H), 1.28 (t, 3H), 1.15-2.10 (m, 16H), 2.30 (bd, 1H), 2.55(m, 2H), 2.72 (m, 1H), 2.86 (m, 1H), 3.20 (s, 2H), 4.18 (q, 2H), 4.20(m, 1H), 4.52 (m, 1H), 4.93 (m, 1H), 4.97 (m, 1H), 5.82 (d, 1H), 6.44(d, 1H).

Preparation 23: Compound 39

Using General Procedure 5, the ester V is compound 38 (200 mg), and theorganometallic reagent is MeMgBr (3M solution in ether, 0.8 ml).Compound 39: δ 0.05 (m, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.86 (d, 3H),0.89 (s, 9H), 1.26 (s, 6H), 1.10-2.07 (m, 16H), 2.30 (bd, 1H), 2.36 (bs,1H), 2.65 (s, 2H), 2.45-2.72 (m, 3H), 2.87 (m, 1H), 4.21 (m, 1H), 4.52(m, 1H), 4.93 (m, 1H), 4.97 (m, 1H), 5.81 (d, 1H), 6.44 (d, 1H).

Preparation 24: Compound 26

Using General Procedure 5, the ester V is compound 38 (164 mg), and theorganometallic reagent is EtMgBr (3M solution in ether, 0.64 ml).Compound 26: δ 0.05 (m, 12H), 0.54 (s, 3H), 0.86 (s, 9H), 0.90 (s, 9H),0.84-0.90 (m, 9H), 1.15-2.10 (m, 20H), 2.15 (s, 1H), 2.30 (bd, 1H),2.40-2.72 (m, 5H), 2.87 (m, 1H), 4.21 (m, 1H), 4.52 (m, 1H), 4.94 (m,1H), 4.98 (m, 1H), 5.81 (d, 1H), 6.44 (d, 1H).

Preparation 25: Compound 40

Using General Procedure 6, the compound V is compound 39, and thechromatographic conditions were: 30 g silica gel, 5% increasing to 10%ethyl acetate in petroleum ether as eluant. Compound 40: δ 0.05 (m,12H), 0.53 (s, 3H), 0.86 (s, 18H), 0.87 (d, 3H), 1.25 (s, 6H), 1.10-2.05(m, 16H), 2.20 (dd, 1H), 2.38 (bs, 1H), 2.64 (s, 2H), 2.30-2.70 (m, 3H),2.81 (m, 1H), 4.18 (m, 1H), 4.36 (m, 1H), 4.85 (m, 1H), 5.17 (m, 1H),6.00 (d, 1H), 6.22 (d, 1H).

Preparation 26: Compound 27

Using General Procedure 6, the compound V is compound 26, and thechromatographic conditions were: 30 g silica gel, 2% increasing to 5%ethyl acetate in petroleum ether as eluant. Compound 27: δ 0.05 (m,12H), 0.53 (s, 3H), 0.87 (s, 18H), 0.75-1.00 (m, 9H), 1.05-2.07 (m,20H), 2.17 (bs, 1H), 2.20 (dd, 1H), 2.40-2.70 (m, 5H), 2.81 (m, 1H),4.20 (m, 1H), 4.36 (m, 1H), 4.85 (m, 1H), 5.16 (m, 1H), 6.00 (d, 1H),6.22 (d, 1H).

Preparation 27: Compound 41

Using General Procedure 3, the alcohol used is compound 7 (1.54 g).Compound 41: δ 0.05 (m, 12H), 0.52 (s, 3H), 0.85 (s, 9H), 0.85 (d, 3H),0.89 (s, 9H), 1.47 (s, 9H), 1.05-2.05 (m, 16H), 2.30 (bd, 1H), 2.55 (dd,1H), 2.86 (m, 1H), 3.48 (m, 2H), 3.93 (s, 2H), 4.21 (m, 1H), 4.53 (m,1H), 4.93 (m, 1H), 4.97 (m, 1H), 5.81 (d, 1H), 6.44 (d, 1H).

Preparation 28: Compound 42

Using General Procedure 5, the ester V is compound 41 (219 mg), and theorganometallic reagent is MeMgCl (3M solution in ether, 1.0 ml).Compound 42: δ 0.05 (m, 12H), 0.53 (s, 3H), 0.85 (s, 9H), 0.85 (d, 3H),0.89 (s, 9H), 1.1-2.05 (m, 26H, including 1.19 (s, 6H)), 2.31 (bd, 1H),2.33 (s, 1H), 2.55 (dd, 1H), 2.87 (m, 1H), 3.22 (s, 2H), 3.45 (t, 2H),4.21 (m, 1H), 4.53 (m, 1H), 4.92 (m, 1H), 4.97 (m, 1H), 5.81 (d, 1H),6.44 (d, 1H).

Preparation 29: Compound 43

Using General Procedure 6, the compound V is compound 42, and thechromatographic conditions were: 30 g silica gel, 10% ether in petroleumether as eluant. Compound 43: δ 0.05 (m, 12H), 0.54 (s, 3H), 0.85 (d,3H), 0.87 (s, 18H), 1.19 (s, 6H), 1.10-2.05 (m, 18H), 2.20 (dd, 1H),2.33 (s, 1H), 2.44 (dd, 1H), 2.82 (m, 1H), 3.22 (s, 2H), 3.45 (t, 2H),4.18 (m, 1H), 4.36 (m, 1H), 4.86 (m, 1H), 5.17 (m, 1H), 6.01 (d, 1H),6.23 (d, 1H).

General Procedure 8A

Conversion of Compounds VI to the corresponding Compound I bydesilylation with tetra-n-butylammonium fluoride (Examples 1-6)

A solution of Compound VI (0.3 mmol) and tetra-n-butylammonium fluoridetrihydrate (1.2 mmol) in THF (10 ml) under N₂ was stirred at 60° C. for1 hour. After cooling, the reaction mixture was partitioned betweenethyl acetate and 2% sodium hydrogen carbonate solution. Work-up andpurification by chromatography gave compound I.

General Procedure 8B

Conversion of Compounds VI to the corresponding Compound I bydesilylation with HF (Examples 7 and 8)

The compound V (ca. 0.2 g) was dissolved in ethyl acetate (0.6 ml) andacetonitrile (8 ml) was added under vigorous stirring. A solution of 5%hydrofluoric acid in acetonitrile/water 8:1 (4.0 ml) was added, and thereaction mixture was stirred under nitrogen at room temperature forminutes. Excess 4N aqueous NaOH solution was added, and the reactionmixture was worked-up (ethyl acetate). The residue was purified bychromatography to give the compound I.

EXAMPLE 1

1(S), 3(R) -Dihydroxy-20(S)- 2-(2-hydroxy-2-methyl-1-propoxy)ethyl!-9,10-seco-pregna-5(Z), 7(E), 10(19)-triene (Compound 101)

Using Procedure 8A: the compound VI is compound 21, and thechromatographic conditions were: 30 g silica gel; 60% ethyl acetate inpetroleum ether as eluant.

Compound 101: δ 0.56 (s, 3H), 0.86 (d, 3H), 1.20 (s, 6H), 1.10-2.40 (m,20H), 2.60 (dd, 1H), 2.83 (m, 1H), 3.23 (m, 2H), 3.50 (m, 2H), 4.23 (m,1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 6.02 (d, 1H), 6.38 (d,1H).

EXAMPLE 2

1(S),3(R)-Dihydroxy-20(S)-2-(2-hydroxy-2-ethyl-1-butoxy)ethyl!-9,10-seco-pregna-5(Z),7(E),10(19)-triene(Compound 102).

Using Procedure 8A: the compound VI is compound 22, and thechromatographic conditions were: 30 g silica gel; 60% ethyl acetate inpetroleum ether as eluant.

Compound 102: 0.56 (s, 3H), 0.85 (d, 3H), 0.86 (t, 6H), 1.15-2.10 (m,22H), 2.15 (s, 1H), 2.31 (dd, 1H), 2.60 (dd, 1H), 2.83 (m, 1H), 3.26 (m,2H), 3.47 (m, 2H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m,1H), 6.02 (d, 1H), 6.38 (d, 1H).

EXAMPLE 3

1(S), 3(R) -Dihydroxy-20(S)-2-(3-hydroxy-3-ethyl-1-pentoxy)ethyl!-9,10-seco-pregna-5(Z), 7(E),10(19)-triene (Compound 103)

Using Procedure 8A: the compound VI is compound 23, and thechromatographic conditions were: 30 g silica gel; ethyl acetate inpetroleum ether as eluant.

Compound 103: δ 0.55 (s, 3H), 0.85 (d, 3H), 0.86 (t, 6H), 1.72 (t, 2H),1.15-2.25 (m, 22H), 2.31 (dd, 1H), 2.60 (dd, 1H), 2.83 (m, 1H), 3.24(bs, 1H), 3.44 (m, 2H), 3.62 (m, 2H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00(m, 1H), 5.33 (m, 1H), 6.01 (d, 1H), 6.37 (d, 1H).

EXAMPLE 4

1(S), 3(R)-Dihydroxy-20(S) - 2-(3-hydroxy-3-ethyl-2,2-difluoro-1-pentoxy)ethyl!-9,10-seco-pregna-5(Z), 7(E),10(19)-triene (Compound 104)

Using Procedure 8A: the compound VI is compound 24, and thechromatographic conditions were: 30 g silica gel; 60% ethyl acetate inpetroleum ether as eluant.

Compound 104: δ 0.54 (s, 3H), 0.85 (d, 3H), 0.93 (t, 6H), 1.15-2.10 (m,22H), 2.29 (dd, 1H), 2.59 (m, 1H), 2.63 (s, 1H), 2.81 (m, 1H), 3.57 (m,2H), 3.79 (m, 1H), 4.22 (m, 1H), 4.42 (m, 1H), 4.99 (m, 1H), 5.31 (m,1H), 6.00 (d, 1H), 6.36 (d, 1H).

EXAMPLE 5

1(S), 3(R) -Dihydroxy-20(S)-2-(2-hydroxy-2-methyl-1-propylthio)ethyl!-9,10-seco-pregna-5(Z), 7(E),10(19)-triene (Compound 107)

Using Procedure 8A: the compound VI is compound 40, and thechromatographic conditions were: 15 g silica gel; 60% ethyl acetate inpetroleum ether as eluant. Compound 107: δ 0.56 (s, 3H), 0.86 (d, 3H),1.27 (s, 6H), 1.10-2.07 (m, 18H), 2.31 (dd, 1H), 2.40 (bs, 1H), 2.66 (s,2H), 2.45-2.72 (m, 3H), 2.83 (m, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00(m, 1H), 5.33 (m, 1H), 6.02 (d, 1H), 6.37 (d, 1H).

EXAMPLE 6

1(S), 3(R) -Dihydroxy-20(S)-2-(2-hydroxy-2-ethyl-1-butylthio)ethyl!-9,10-seco-pregna-5(Z), 7(E),10(19)-triene (Compound 106)

Using Procedure 8A: the compound VI is compound 27, and thechromatographic conditions were: 15 g silica gel; 60% ethyl acetate inpetroleum ether as eluant. Compound 106: δ 0.55 (s, 3H), 0.86 (d, 3H),0.88 (t, 6H), 1.15-2.20 (m, 23H), 2.31 (dd, 1H), 2.45-2.70 (m, 5H), 2.83(m, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 6.02(d, 1H), 6,38 (d, 1H).

EXAMPLE 7

1(S), 3(R)-Dihydroxy-20(S)-3-(2-hydroxy-2-methyl-1-propoxy)-prop-1E-en-1-yl!-9,10-seco-pregna-5(Z),7(E), 10(19)-triene (Compound 105)

Using Procedure 8B: the compound VI is compound 25, and thechromatographic conditions were: 30 g silica gel; ethyl acetate aseluant. Compound 105: δ 0.51 (s, 3H), 0.93 (d, 3H), 1.17 (s, 6H),1.10-2.15 (m, 17H), 2.29 (bd, 1H), 2.56 (dd, 1H), 2.80 (bd, 1H), 3.21(s, 2H), 3.96 (m, 2H), 4.20 (m, 1H), 4.41 (m, 1H), 4.98 (bt, 1H), 5.30(m, 1H), 5.45 (m, 1H), 5.55 (m, 1H), 5.99 (d, 1H), 6.35 (d, 1H).

EXAMPLE 8

1(S), 3(R)-Dihydroxy-20(S)-3-(2-hydroxy-2-methyl-1-propoxy)-prop-1-yl!-9,10-seco-pregna-5(Z), 7(E),10(19)-triene (Compound 108)

Using Procedure 8B: the compound VI is compound 43, and thechromatographic conditions were: 30 g silica gel; ethyl acetate aseluant. Compound 108: δ 0.54 (s, 3H), 0.85 (d, 3H), 1.10-2.06 (m, 26H,including 1.20 (s, 6H)), 2.31 (m, 1H), 2.32 (s, 1H), 2.60 (dd, 1H), 2.83(m, 1H), 3.23 (s, 2H), 3.45 (t, 2H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00(m, 1H), 5.33 (m, 1H), 6.02 (d, 1H), 6.38 (d, 1H).

EXAMPLE 9

Capsules Containing Compound 105

Compound 105 was dissolved in arachis oil to a final concentration of 10μg compound 105/ml oil. 10 Parts by weight of gelatine, 5 parts byweight glycerine, 0.08 parts by weight potassium sorbate, and 14 partsby weight distilled water were mixed together with heating and formedinto soft gelatine capsules. These were then filled each with 100 μl ofthe compound 105 in oil solution, such that each capsule contained 1 μgcompound 105.

EXAMPLE 10

Dermatological Cream Containing Compound 105

In 1 g almond oil was dissolved 0.5 mg compound 105. To this solutionwas added 40 g of mineral oil and 20 g of self-emulsifying beeswax. Themixture was heated to liquify. After the addition of 40 ml hot water,the mixture was mixed well. The resulting cream contains approximately 5μg of compound 105 per gram of cream.

What we claim is:
 1. A compound of formula I ##STR4## in which formulathe "¤" indicates that this carbon may be modified, and the moiety Ureplaces the 24-methylene of 1α,25-dihydroxy-20-epi-vitamin D₃ andstands for (CH₂)_(n) --Y--(CH₂)_(m), where n is 0, 1 or 2, m is 1 or 2,and Y is oxygen or sulphur; and derivatives formed by replacing eitherthe 22-methylene or the 23-methylene by an oxygen or by replacing 22-and 23-methylene with --CH═CH--; R' is methyl or ethyl; and in which oneor more carbon atoms directly bonded to C-25 may optionally besubstituted with one or more fluorine atoms; and derivatives of I inwhich one or more of the hydroxy groups are masked as groups which canbe reconverted to hydroxy groups in vivo.
 2. A compound of formula Iaccording to claim 1 in which C-22 and C-23 are both carbon, m standsfor 1 and Y is oxygen.
 3. A compound according to claim 2 which is1(S),3(R)-Dihydroxy-20(S)-3-(2-hydroxy-2-methyl-1-propoxy)-prop-1E-en-1-yl!-9,10-seco-pregna-5(Z),7(E),10(19)-triene.4. A diastereoisomer of a compound according to claim 1 in pure form. 5.A pharmaceutical composition containing an effective amount of at leastone compounds of formula I according to claim 1, together with apharmaceutically acceptable, non-toxic carrier.
 6. A pharmaceuticalcomposition according to claim 5 in dosage unit form containing from 0.1ppm to 0.1% by weight of the dosage unit of a compound of formula I. 7.A method for the treatment of inflammatory diseases or diseasescharacterized by abnormal cell differentiation or cell proliferationwhich comprises administering to a patient in need of such treatment aneffective amount of a pharmaceutical composition according to claim 1.